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The role of Dynamin in muscle remodeling and maintenance


Membrane trafficking, the movement of transport vesicles between membrane compartments, is essential for cell remodeling and maintenance. Specialized membrane compartments are particularly important in large, highly differentiated myofibers to support muscle contraction and integrity. Transversal (T-) tubule membranes allow for synchronized myofibril contraction, whereas integrin complex adhesions at localized sites on the plasma membrane help maintain muscle attachments under mechanical stress. The organization of muscle-specific membrane compartments is compromised in three similar human myopathies independently associated with recessive MTM1 and AMPH2 or dominant DNM2 mutations. Interestingly, all three genes have well-established membrane-related roles. Considering the similar disease associations, MTM1, AMPH2 and DNM2 may potentially function together by an unknown membrane trafficking mechanism important for myofiber organization. Whereas MTM1 PI3-phosphatase has been investigated in muscle, a possible muscle-specific requirement remains unknown for Dynamin 2 (DNM2), a large GTPase widely known for its membrane fission role in endocytosis. Here, I explored muscle-specific roles for shibire (shi), the single Dynamin in flies. I found that Shi localizes to endocytic sites within fly muscle, and that either shi depletion or overexpression disrupts myofiber attachments that rely in integrin localization and traffic. Overexpression of Shi or a human DNM-related mutant, Shi-E364K, induced phenotypes consistent with ectopic endocytic functions, including accumulation of abnormal integrin- and Shi-positive inclusions. Interestingly, the Shi overexpression defects phenocopied and were enhanced by mtm RNAi, while inclusion defects were suppressed by either shi or Class II PI3-kinase Pi3K68D co-depletion. These and ongoing studies begin to uncover a common endocytic pathway for mtm, Pi3K68D and shi relevant to muscle cell remodeling, aging, maintenance and disease

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